AKAP Signaling Islands: Venues for Precision Pharmacology

Regulatory enzymes often have different roles in distinct subcellular compartments. Yet, most drugs indiscriminately saturate the cell. Thus, subcellular drug-delivery holds promise as a means to reduce off-target pharmacological effects. A-kinase anchoring proteins (AKAPs) sequester combinations of signaling enzymes within subcellular microdomains. Targeting drugs to these ‘signaling islands’ offers an opportunity for more precise delivery of therapeutics. Here, we review mechanisms that bestow protein kinase A (PKA) versatility inside the cell, appraise recent advances in exploiting AKAPs as platforms for precision pharmacology, and explore the impact of methodological innovations on AKAP research. Protein kinase A (PKA) is a versatile and spatially restricted cell signaling enzyme.A‐kinase anchoring proteins (AKAPs) define which substrates have access to PKA.Local signaling islands shape the cellular role of PKA and other AKAP-associated enzymes.Recent in situ pharmacological strategies suggest that AKAPs can be used as platforms for drug targeting.